Viral Oncology: molecular biology and pathogenesis of post-transplant lymphoproliferative disorder (PTLD)

Post-transplantation lymphoproliferative disorder (PTLD) is a rare but life-threatening disorder following solid organ (SOT) and hematopoietic stem cell transplantation (HSCT). The disorder is caused by drug-induced reduced immune surveillance leading to an uncontrolled proliferation of lymphocytes. Although rare, incidence has clearly increased during the last two decades with estimated incidence rates of 1-20% in SOT recipients. After it is histologically confirmed, PTLD is categorized by using the 4 categories provided by the current 2017 World Health Organization (WHO) classification: nondestructive PTLD, polymorphic PTLD, monomorphic PTLD and classic Hodgkin’s like PTLD. Despite this huge heterogeneity in pathological presentation, almost 90% of the PTLD cases are monomorphic diffuse large B cell lymphoma (DLBCL) subtypes. Although not required for diagnosis of PTLD, the oncogenic Epstein Barr virus (EBV) is a key pathogenic driver in a substantial proportion of cases (60-70%), mainly in the early onset (diagnosis in the first year following transplantation). Among these patients, PTLD is almost systematically of donor origin and is mostly associated with EBV. T-cell depletion strategies and the type of donation (higher risk in unrelated or mismatched HSCT) and older age are considered the most important risk factors. Other risk factors, including non-EBV infections, have been associated with PTLD in some studies but not consistently. Although EBV plays a clear role in PTLD, other associated viral infections could trigger this disorder. For instance, EBV reactivation in HSCT has been proposed to be linked to human cytomegalovirus (HCMV) reactivation. Recently, DNA viruses associated with EBV‐negative PTLD were determined using metagenomic shotgun sequencing (MSS) of archived formalin‐fixed paraffin‐embedded tissue samples from PTLD patients. Multiple viruses were detected in PTLD tissues by MSS. Anellovirus positivity, not EBV positivity, was associated with worse patient survival in a series of 69 PTLD tissue samples collected between 1991 and 2015 from 60 subjects. A systematic evaluation of DNA viruses that are present in serum samples from transplant patients that developed PTLD as (co)factors for EBV reactivation and development of PTLD has not yet been performed and is necessary to implement pre-emptive strategies to reduce the risk of this disorder. The general aims of this project are (1) to find reliable biomarkers that can predict development of SOT-related PTLD, (2) to identify prognostic biomarkers predicting response to treatment and (3) to explore new targeted treatments for patients relapsing after first line therapy. To this end, we aim to provide an integrated insight in the genomic landscape of both EBV+ and EBV- PTLD, which will be achieved by characterizing both the human genome as well as the virome of PTLD. This research is performed in collaboration with Dr Vikas Dharnidharka from Washington University School of Medicine & St. Louis Children’s Hospital, who applied for a National Institute of Health (NIH) grant, which was based on microbial metagenomics shotgun sequencing (MSS), aiming to search for potential non-EBV viruses as drivers for EBV- PTLD following SOT. Approximately 600 PTLD biopsies collected retrospectively (including complete clinical information) will be available to perform additional research to study other etiological pathways on this unique collection of biopsies, corresponding plasma samples and extensive clinical information, as suggested by NIH. Our Leuven research consortium will carry out investigations on this unique collection of samples to provide maximal research on the samples, being the characterization of the human genome in these PTLD biopsies performed at Prof. Jan Cools’ laboratory.